P498: INCIDENCE, RISK FACTORS AND OUTCOMES OF SECOND NEOPLASMS IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA: THE PETHEMA-PALG EXPERIENCE.
Authors: Marta Sobas, Wanda Knopinska-Posluszny, Beata Piątkowska-Jakubas, Gert Ossenkoppele, Flor García-Álvarez, María Elena Amutio Díez, Mar Caballero, David Martinez-Cuadrón, Eliana Aguiar, Jose Gonzalez Campos, Ana Garrido Diaz, Lorenzo Algarra, Olga Salamero, Javier de la Serna, Maria Jose Sayas Lloris, Manuel Mateo Perez Encinas, Susana Vives Polo, Veronica Gonzalez DE LA Calle, Jorge Labrador, Ana Inés Prado, Lucía Celebrin, Jiri Mayer, Graca Luiza O P Neto Vasconcelos Esteves, Almudena de Laiglesia, Juan Miguel Bergua Burgues, Maria Luz Amigo, Carlos Rodriguez Medina, Marta Polo, Agnieszka Pluta, Edyta Cichocka, Marek Skarupski, Miguel A Sanz, Pau Montesinos
Journal: HemaSphere (2023)

Background: Acute promyelocytic leukaemia (APL) has a cure rate greater than 80%, being the most important challenges preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). The reported incidence of s-NPLs in APL is low, with poor outcomes. Data on risk factors (including”chemo-free” strategies) is limited. Aims: Incidence, main outcomes and risk factors for development of s-NPLs after achievement of first CR in APL patients. Methods: We performed a retrospective analysis of 2670 unselected APL patients, diagnosed and treated with PETHEMA protocols: chemotherapy based (APL1996, 1999, 2005, 2012 and 2017 for high risk) and “chemo free” ATO+ATRA (2017 for low/intermediate risk). Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Diagnosis of second myelodysplastic syndromes/acute myeloid leukaemia (s-MDS/AML) was made according to the WHO criteria and other second haematological malignancies or solid tumours were confirmed by histopathological analyses. Time-to-event analyses were performed using the Kaplan-Meier method and, for comparisons, log-rank test. The probability of developing s-NPL was also estimated by the cumulative incidence (CI) method, and death in CR and relapse of APL were considered competing risks. Multivariate analysis was performed using the Cox proportional hazards model. All tests were performed in R version 4.2.1. Results: Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8-231.1): 43.3 (range: 2.8-113.9) for s-MDS/AML and 61.7 (range: 7.1 – 231.1) for solid tumour. The 5-years CI of all s-NPLs was of 4.43% and 10-years of 7.92%. The CI according to protocols (APL1996, 1999, 2005, 2012, 2017) was as follow: 4.33% vs 3.69% vs 4.91% vs 5.14% vs 1.27% (5-years) and 8.94% vs 6.07% vs 9.61% vs 8.83% vs incomplete observation (10-years). Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other haematological neoplasms, 54 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorrectal, followed by lung and breast cancer. In case of s-MDS/AML the most frequent cytogenetic abnormalities were complex karyotype, monosomy of 7 and del 7q. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months (Fig.A). In patients developing s-NPLs there was a slight predominance of female sex (57.6%) and the median age at time of diagnosis of APL was higher vs APL without s-APLs: 55 (range from 13 to 84) vs 43 (range from 2 to 87) years. There were no difereces in the Sanz risk score distribution. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001; Fig B) as an independent prognostic factors for s-NPLs. In multivariate analysis there were no significant differences of s-NPLs development between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p =0.932; Fig C) probably due to low number and shorter follow-up of patients treated with ATO+ATRA regimens. Summary/Conclusion: The s-NPLs are relatively frequent and severe late complication in APL. Age >= 35 years is a potential risk factor for development of s-NPLs. Chemotherapy free regimens had lower CI of s-NPLs at 5 years, nevertheless more data and follow-up are required. APL survivors should be carefully screened for s-NPLs once APL is cured.Keywords: Chemotherapy, Arsenic trioxide, Acute promyelocytic leukemia, Second malignancy